DE19750007A1 - New poly:alkylene glycol-modified quinine or quinidine derivatives - Google Patents

Abstract

Polyalkylene glycol-protected dihydroquinine or dihydroquinidine derivative ligands of formulae (I) (based on 2-biphenylyl-pyrimidine) and (IV) (based on 2,3-bis-(biphenylyl)-pyrazino-(2,3-d)-pyridazine) are new. T = ester residue of formula (a), groups T being same or different in (IV); m = 50-150; n = 1-5; z = 0-4; R1-R3 independently = H, 1-5C alkyl, 3-8C cycloalkyl, aryl, aralkyl, alkaryl or (1-8C)-alkylalkoxy (sic); R = dihydroquinine or dihydroquinidine derivative residue of formula (II) or (III) respectively; R' = H, 1-5C alkyl, 3-8C cycloalkyl, aryl, aralkyl or alkaryl.

Description

The invention relates to a process for the preparation of dihydroquinine derivatives of the formula (I)

where m is an integer in the range from 50 to 150, n is an integer in the range from 1 to 5 and z is an integer in the range from 0 to 4,
R ₁ , R ₂ and R _3, independently of one another, are the same or different, and R ₂ and R _{3 are} variable depending on n, H, (C ₁ -C ₅ ) -alkyl, linear or branched, (C ₃ -C ₈ ) -cycloalkyl , Aryl, aralkyl, alkylaryl or (C ₁ -C ₈ ) alkylalkoxy, linear or branched
and R is a radical of formula (II) or (III)

where R 'can be H, (C ₁ -C ₅ ) alkyl, linear or branched, (C ₃ -C ₈ ) cycloalkyl, aryl, aralkyl or alkylaryl,
and for the preparation of dihydroquinidine derivatives of the formula (IV)

wherein m and o, independently of one another, are identical or different integers in the range from 50 to 150, n and p, independently of one another, are identical or different integers in the range from 1 to 5 and z and y, independently of one another, are identical or different integers in the range from 0 to 4 are and
R, R ₁ , R ₂ and R _{3 have} the meaning given for formula (I), where R ₂ and R _{3 are} additionally variable as a function of o.

The invention further relates to the method of the invention available new dihydroquinine or Dihydroquinidine derivatives of the formulas (I) and (IV) and their use for the enantioselective dihydroxylation of Double bonds.

Chem. Rev. 1994, 94, 2483 (Sharpless et al.) monomeric catalyst systems for enantioselective  Dihydroxylation based on dihydroquinine and Dihydroquinidine derivatives described. Although the Very high enantioselectivity of the catalysts used the ligands used are high disadvantageous when they are not or bad Have it recycled and if so, then only with a bad one Yield (liquid-liquid extraction yield clearly below 80%).

In J. Am. Chem. Soc. 1996, 118, 7632-3 (Janda et al.) the production of MeO-Peg-protected dihydroquinine as well its application in enantioselective dihydroxylation of compounds containing double bonds mentioned. The catalyst system presented there achieved at enantioselective dihydroxylation of standard compounds up to <30% worse ee values than that of originally Sharpless et al. found systems.

Table 1

Table 1 shows those of Janda et al. and Sharpless et al. achieved the best enantioselectivities in the Dihydroxylation of standard compounds with their Catalyst or ligand systems shown. Obviously, the polymer bond leads to the Ligand systems with optimized for the individual systems Reaction conditions to drastically worse ee values.

The object of the invention was therefore to provide a method for Development of a catalyst system to develop which ee values similar to those of the original Sharpless process in dihydroxylation and which in simpler Way to be separated from the reaction medium and so for a new reaction cycle is available. task the invention was also the specification of new Catalyst systems used for asymmetric dihydroxylation of double bonds can serve as well as the way their use.

These and other unspecified issues were resolved Tasks with a procedure that reflects the characteristics of the characterizing part of claim 1. Advantageous process modifications are shown in the Claim 1 related claims under protection. In terms of product technology, claims 8 and 9 provide Proposed solutions for those on which the invention is based Problem. Claims 11-15 disclose novel ones Uses of the invention.

By using compounds of formula (V) or (VI) Compounds of the general formula (VII) esterified (compare scheme 1), it is extremely advantageous To obtain compounds of the formulas (I) and (IV), which in enantioselective dihydroxylation with not without further predictable success can be used.  

Scheme 1

The compounds of the formulas (V) and (VI) in turn are obtained by reacting compounds of the formulas (VIII) and (IX) with the aromatic (X) in the presence of catalytic amounts of a palladium ^{± 0} compound (see scheme 2) and then the silyl protective group is removed with a fluoride-containing agent. The use of tetrabutylammonium fluoride is particularly preferred.

Scheme 2

The palladium compound used advantageously consists of the elemental metal and a complexing ligand from the series of triphenylphosphines or triphenylphosphites. The compound [Pd (PPh ₃ ) ₄ ] is very particularly preferred.

The compounds of formulas VIII and IX can be found in get different ways.

In a first preferred embodiment, the process of the invention is characterized in that the compounds of the formulas (VIII)

by reaction of substances of the formula (XII)

with DHQ (II) or DHQD (III).

In a second preferred embodiment, the process of the invention is characterized in that the compound of the formula (IX)

by reaction of substances of the formula (XIII)

with DHQ (II) or DHQD (III).

The substances of the formulas (XIII) and (XII) can be analogous methods known from the literature (J. Org. Chem. 1993, 58, 3785) starting from 4-bromobenzonitrile or from pyrazine-2,3- dicarboxylic acid according to z. B. J. Org. Chem. 1995, 60, 3940 be synthesized.  

The invention further relates to the new Ligand systems of the formulas (I) and (IV).

The invention also relates to the use of the new Ligand systems (I) and (IV), which it advantageously in Presence of oxidizing agents such as N-methylmorpholine-N- oxide, potassium hexacyanoferrate and / or potassium osmate in one Allow solvent mixture, a double bond in very high enantiomeric excesses to dihydroxylate. A preferred use according to the invention provides that one dihydroxylation in a mixed solvent comprising one or more solvents from the group, Water, alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, sec-butanol, tert-butanol, Isobutanol, n-pentanol, ethers such as diethyl ether, Tetrahydrofuran, dimethoxyethane, dioxane, ketones such as Acetone, methyl isobutyl ketone, ethyl ketone, diisopropyl ketone or esters such as acetoacetic ester or ethyl acetate as well halogenated alkanes such as methylene chloride, chloroform, Trichlorethylene performs. Preferred Solvent mixtures are u. a. Water and tert-butanol or water and acetone. This is particularly useful Solvent mixture of at least two of the aforementioned Solvent. In addition, the catalysts (I) and (IV) after the dihydroxylation in a particularly simple manner by adding a non-polar organic solvent to the Reaction mixture can be precipitated. Preferred to this usable solvents include z. B. alkanes, such as hexane, Cyclohexane, methylcyclohexane; Petroleum ether or ether, MTBE, tetrahydrofuran or diethyl ether are preferred as well as DME; Ketones such as acetone, MIBK or ethyl methyl ketone as well as diisopropyl ketone; Esters, such as ethyl acetate or Acetoacetic ester. The temperature of the dihydroxylation is at -20 ° to + 20 ° C, temperatures of -10 ° are preferred to + 10 ° C and temperatures are particularly preferred from +20 to -2 ° C. The recycling of the ligands is accomplished by Scheme 3 illustrates.  

Scheme 3

Table 2

Table 2 shows those obtained as in Example 1 Enantioselectivities of Dihydroxylation of Standard connections compared to those with the Sharpless et al. attainable Values. The ee values according to the invention are only slightly lower.

After separation, the ligands run through the reaction mixture Precipitation with a non-polar solvent in over 98% This can yield a new dihydroxylation be used, which is extremely advantageous and yet was unexpected.  

Ligand (IV) used

Ligand (IV) used

Table 3 shows the results obtained as in Example 1 the dihydroxylation of styrene six times sequential use of the ligand (IV). The easy one A decrease in the ee values is due to an alkaloid loss minor ester hydrolysis under basic Reaction conditions attributed.

The reaction can optionally be carried out in suitable plants operated continuously by using the Polymer ligands of the formulas (I) or (IV) in one Loop reactor works and the solution with that too hydroxylating compound before dihydroxylation contacted and after the reaction by appropriate Devices with or without prior failure of the Ligands but with their retention in the loop reactor separates.

It is therefore very advantageous and very good Yield the expensive new ligand systems (I) and (IV) in the highly enantioselective dihydroxylation and then in a simple way to recycle what for  more economical production of enantioselective enriched 1,2-diols.

The following examples serve for detailed Explanation of the invention.

A: Reaction example example 1 Dihydroxylation of styrene

A mixture of 167 mg (15 µmol) (MeOPEG) ₂ DPP (DHQD) ₂ , 0.99 g (3 mmol) potassium hexacyanoferrate (III), 0.41 g (3 mmol) potassium carbonate and 3.7 mg (10 µmol) potassium osmate in 10 ml t BuOH water 1: 1 is cooled to 0 ° C with an ice bath. 104 mg (1 mmol) of styrene are slowly added dropwise to this reaction solution with vigorous stirring. After 3 hours, the mixture is carefully mixed with 1 g of sodium disulfite at 0 ° C. and warmed to RT. It is diluted with 10 ml of methylene chloride and separated from the aqueous phase. The ligand is precipitated from the organic phase by slow dropwise addition of MTBE with vigorous stirring and is recovered in good yield (164 mg, 98%). The dihydroxylated styrene remains in the organic solution and can be isolated by concentrating and chromatography on silica gel with MTBE in yields of up to 127 mg (92% of theory) and 98% ee.

B: Preparation of the ligands Example 2 Synthesis of 4-bromobenzamidine hydrochloride

To a solution of 0.35 g (15 mmol) sodium in 150 ml Methanol became 27.30 g (150 mmol) of 4-bromobenzonitrile given. After stirring at RT for 48 h, 8.00 g (150 mmol)  Ammonium chloride was added and an additional 24 hours touched. Excess ammonium chloride was filtered off and with 100 ml each of methanol and methylene chloride washed. After removing the solvents, one obtains a colorless solid, which is then mixed with 150 ml Diethyl ether was washed. The yield was 11.76 g (50 mmol, 33% of theory).

After concentration, 16.57 g (91 mmol) of 4-bromobenzonitrile could be recovered from the ethereal washing solution.
¹ H NMR (300 MHz, DMSO-d ₆ ): δ 3.17 (s, 4H; NH), 7.80-7.92 (m, 4H; Ar-H).

Synthesis of 2- (4-bromophenyl) -5-phenyl-4,6- dihydroxypyrimidine

10.98 g (47 mmol) of 4-bromobenzamidine hydrochloride and 11.15 g (47 mmol) of ethyl phenylmalonic acid were introduced in succession into a solution of 3.45 g (150 mmol) of sodium in 100 ml of methanol. The mixture was heated to 80 ° C for 12 h. The deep yellow reaction solution was then filtered off from sodium chloride formed and the pyrimidine was precipitated with 10 ml of 2 molar hydrochloric acid as an intensely yellow solid. The solid was washed successively with water, ethanol and diethyl ether. Yield: 12.70 g (37 mmol, 79% of theory) yellow solid. The pyrimidine is insoluble in all organic solvents and water tested.
Mp: <230 ° C
HRMS (FD):
calculated for C ₁₆ H ₁₁ BrN ₂ O ₂ (M⁺), 342,0009;
found 342.0009.

Synthesis of 2- (4-bromophenyl) -5-phenyl-4,6-dichloropyrimidine

A mixture of 11 g (32 mmol) of 2- (4-bromophenyl) -5-phenyl-4,6-dihydroxypyrimidine, 120.6 g (0.79 mmol) of phosphoryl chloride and 10.26 g (69 mmol) of N, N-diethylaniline was stirred for 48 h Heated to 130 ° C. Excess phosphoryl chloride was distilled off and the hot residue was quickly poured onto a sodium hydroxide / ice mixture (27 g / 270 g) while stirring. The mixture was then extracted three times with 60 ml of diethyl ether each time and the combined organic phases were successively washed neutral with hydrochloric acid and water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Recrystallization of the residue from ethyl acetate / n-hexane gave 9.12 g (24 mmol, 75% of theory) of colorless needles.
Mp: 133 ° C
Elemental analysis: C ₁₆ H ₉ Cl ₂ BrN ₂ (380.07 g / mol):
calcd. C 50.56, H 2.39, N 7.37;
found C 50.54, H 2.47, N 7.38.

Synthesis of 2- (4-bromophenyl) -5-phenyl-4,6-bis- (dihydroquinidinyl) pyrimidine

To 1.62 g (4.26 mmol) of 2- (4-bromophenyl) -5-phenyl-4,6-dichloropyrimidine and 2.78 g (8.53 mmol) of dihydroquinidine in 25 ml of toluene were added 1.8 g (13 mmol) of potassium carbonate and the mixture became 2 h heated to 130 ° C. Then 0.73 g (13 mmol) of potassium hydroxide were added and the mixture was boiled on a water separator for 12 h. The toluene was distilled off, the residue was taken up in 15 ml of methylene chloride and extracted three times with 10 ml of water each time. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by column chromatography (silica gel; eluent: chloroform-ethanol 9: 1) gave 3.06 g (3.2 mmol, 75% of theory) of a pale yellow solid.
Mp: 125-128 ° C.

Synthesis of 2- (4-hydroxybiphenyl) -5-phenyl-4,6- bis (dihydroquinidinyl) pyrimidine

To a solution of 1.44 g (1.5 mmol) of 2- (4-bromophenyl) -5-phenyl-4,6-dichloropyrimidine and 0.132 g (0.11 mmol) of tetrakis (triphenylphosphine) palladium in 15 ml of 2 molar sodium carbonate solution and 45 ml of toluene slowly added 0.475 g (1.88 mmol) of 4- (tert-butyldimethylsilyloxy) phenylboronic acid in 21 ml of methanol. The mixture was then heated to reflux for 24 h. After cooling, the mixture was diluted with 50 ml of methylene chloride and water. The separated aqueous phase was extracted three more times with 10 ml of CH ₂ Cl ₂ . The combined organic phases were dried over MgSO ₄ , filtered off and concentrated in vacuo. Chromatography on silica gel with MTBE (removal of the excess boronic acid) gave a pale yellow solid. It was dissolved in 35 ml of THF and 3 ml (3 mmol) of tetrabutylammonium fluoride (1 molar in THF) were slowly added at 0 ° C. The mixture was then stirred for 15 min at 0 ° C and 45 min at RT. After quenching with 30 ml H ₂ O, the THF was removed in vacuo and the residue was extracted three times with 10 ml methylene chloride. The collected organic phases were washed with 30 ml H ₂ O, dried over MgSO ₄ , filtered and concentrated in vacuo. Purification by column chromatography (silica gel; eluent: chloroform-ethanol 9: 1) gave 1.09 g (1.13 mol, 75% of theory) of a pale yellow solid.
Mp: 178 ° C.

Synthesis of [2- (4-hydroxybiphenyl) -5-phenyl-4,6- bis (dihydroquinidinyl) pyrimidine] polyethylene glycol succinate

To a mixture of 1.95 g (2 mmol) 2- (4-hydroxybiphenyl) -5-phenyl-4,6-bis (dihydroquinidinyl) pyrimidine, 5.10 g (1 mmol) succinic acid polyethylene glycol ester (monoester) and 0.024 g (0.2 mmol) 4-Dimethylaminopyridine (DMAP) was added 0.454 g (2.8 mmol) of dicyclohexylcarbodiimide (DCC). The solution was stirred at RT for 12 h. The precipitated dicyclohexylurea was filtered off. Tert-butyl methyl ether (MTBE) was then slowly added dropwise to the filtrate with vigorous stirring, and the precipitate which had separated out was filtered off. The pale yellow solid was taken up twice in a little methylene chloride and again precipitated with MTBE. 5.63 g (0.93 mmol, 93% of theory) of a slightly yellow solid are obtained.
Mp: 56-59 ° C
¹ H NMR (300 MHz, CDCl ₃ ) δ = 0.66 (t, J = 7.2 Hz; 6 H), 0.92 (m, 4H), 1.19-1.83 (m, 10H), 1.95 (m, 2H), 2.48 -3.01 (m, 12H), 3.2-3.9 (polyethylene glycol peaks), 6.9-7.75 (m, 21H), 8.05 (d, J = 9.04 Hz; 2H), 8.79 (m, 2H).

Example 3 Synthesis of 2,3-bis (4-bromophenyl) -5,8-dihydroxypyrazino- [2,3-d] pyridazine

A solution of 7.11 g (50 mmol) of 4,5-diamino-3,6-dihydroxypyridazine and 20 g (54 mmol) of 4,4'-dibromobenzil in 400 ml of glacial acetic acid was heated to 110 ° C. for 5 h (after 10 min it forms a yellow precipitate). It was slowly cooled to RT, the precipitate was filtered off, washed twice with 50 ml of glacial acetic acid and twice with n-hexane. 19.03 g (40 mmol, 80% of theory) of a yellow solid are obtained.

Mp: <240 ° C
Elemental analysis: C ₁₈ H ₁₀ Br ₂ N ₄ O ₂ (474.11 g / mol):
calcd. C 45.60, H 2.13, N 11.82;
found C 45.81, H 2.29, N 11.85.

Synthesis of 2,3-bis (4-bromophenyl) -5,8-dichloropyrazino- [2,3-d] pyridazine

A mixture of 18.00 g (38 mmol) of 2,3-bis (4-bromophenyl) -5,8-dihydroxypyrazino- [2,3-d] pyridazine and 15.81 g (76 mmol) of phosphorus pentachloride in 200 ml of phosphoryl chloride was mixed for 90 min heated to 120 ° C. The phosphoryl chloride was then removed in vacuo and the residue was taken up in 50 ml of methylene chloride. 6 g of basic aluminum oxide were added, and after filtering through silica gel, 17.67 g (34 mmol, 91% of theory) of a yellow solid were obtained.
Mp: 214-218 ° C.

Synthesis of 2,3-bis (4-bromophenyl) -5,8-bis- (dihydroquinidyl) pyrazino [2,3-d] pyridazine

A solution of 0.734 g (2.25 mmol) dihydroquinidine and 0.581 g (5 mmol) N, N, N ', N'-tetramethylethylenediamine in 16 ml dimethoxyethane was cooled to -50 ° C and slowly with 1.4 ml (2.25 mmol) N- Butyllithium (15% solution in n-hexane) added. The red solution was stirred for 15 min, warmed to RT and 0.511 g (1 mmol) of 2,3-bis (4-bromophenyl) -5,8-dichloropyrazino- [2,3-d] pyridazine was added. The mixture was then heated to reflux for 4 h, cooled and diluted with 5 ml of water and 25 ml of methylene chloride. It was washed with 20 ml of saturated aqueous sodium hydrogen carbonate solution and the aqueous phase was extracted three times with 20 ml of methylene chloride. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (silica gel; eluent: chloroform-ethanol 9: 1) gave 0.796 g (0.73 mmol, 73% of theory) of a yellow solid.
Mp: 176-180 ° C

Synthesis of 5,8-bis (dihydroquinidinyl) -2,3-bis- (4- hydroxybiphenyl) pyrazino [2,3-d] pyridazine

To a solution of 19.56 g (18 mmol) 2,3-bis (4-bromophenyl) -5,8-bis- (dihydroquinidyl) pyrazino [2,3-d] pyridazine and 0.5 g (0.433 mmol) tetrakis (Triphenylphosphine) palladium in 500 ml of toluene and 200 ml of 2 molar sodium carbonate solution were slowly added 13.56 g (54 mmol) of 4- (tert-butyldimethylsilyloxy) phenylboronic acid in 800 ml of methanol. The mixture was then heated to reflux for 24 h. After cooling, the separated aqueous phase was extracted three times with 100 ml of methylene chloride, the combined organic phases were dried over MgSO ₄ , filtered and concentrated in vacuo. Chromatography on silica gel with MTBE (removal of the excess boronic acid) gave a yellow solid. It was dissolved in 200 ml of THF and 72 ml (72 mmol) of tetrabutylammonium fluoride (1 molar in THF) were slowly added at 0 ° C. The mixture was then stirred for 15 min at 0 ° C and 45 min at RT. After quenching with 350 ml of water, the THF was removed in vacuo and the residue was extracted with 300 ml of ethanol-methylene chloride 1: 1. The organic phase was washed three times with 100 ml of water, dried over MgSO ₄ , filtered and concentrated in vacuo. Purification by column chromatography (silica gel; eluent: chloroform-ethanol 8: 2) gave 13.68 g (12.2 mmol, 68% of theory) of a yellow solid.
Mp: 204-209 ° C.

Synthesis of [5,8-bis (dihydroquinidinyl) -2,3-bis- (4- hydroxybiphenyl) pyrazino [2,3-d] pyridazine] - polyethylene glycol succinate

To a mixture of 1.34 g (1.2 mmol) of 5,8-bis (dihydroquinidinyl) -2,3-bis (4-hydroxybiphenyl) pyrazino- [2,3-d] pyridazine, 13.26 g (2.6 mmol ) Polyethylene glycol succinate (monoester) and 32 mg (0.26 mmol) DMAP were added to 2.7 g (13 mmol) DCC. The mixture was stirred at RT for 48 h. The precipitated dicyclourea was filtered off. MTBE was then slowly added dropwise to the filtrate with vigorous stirring, and the precipitate which had separated out was filtered off. The yellow solid was taken up twice in a little methylene chloride and again precipitated with MTBE. 12.24 g (1.10 mmol, 92% of theory) of a yellow solid were obtained.
Mp: 55-58 ° C.

Synthesis of 4-bromophenol tert-butyldimethylsilyl ether

29.4 g (432 mmol) of imidazole were added to a solution of 31.14 g (180 mmol) of 4-bromophenol and 32.55 g (216 mmol) of tert-butyldimethylsilyl chloride in 600 ml of methylene chloride. The mixture was then stirred at RT for 12 h. After quenching with 1000 ml of water, the aqueous phase was separated and extracted three times with 200 ml of MTBE. The combined organic phases were washed with saturated sodium chloride solution, dried over MgSO ₄ , filtered and concentrated in vacuo. Purification by column chromatography (silica gel; eluent: MTBE) gave 50.15 g (17.4 mmol, 97% of theory) of clear, colorless oil.
Elemental analysis: C ₁₂ H ₁₉ BrOSi (287.27 g / mol):
calcd. C 50.17 H 6.67
found C 50.24 H 6.70.

Synthesis of 4- (tert-butyldimethylsilyloxy) - phenylboronic acid

0.5 ml of 5.75 g (20 mmol) of 4-bromophenol tert.butyldimethylsilyl ether and a drop of 1,2-dibromoethane were added to a suspension of 0.53 g (22 mmol) of magnesium shavings in 200 ml of THF. To start the reaction, this mixture was heated briefly to reflux. The rest of the aryl bromide was then slowly added dropwise. After the addition had ended, the mixture was heated under reflux for a further 1 h. The copper-colored solution was cooled to RT and slowly added dropwise to a solution of 10.39 g (0.1 mol) trimethyl borate in 50 ml THF cooled to -78 ° C. Overnight was slowly allowed to come to RT. It was quenched with 30 ml of water and the THF was removed in vacuo. The residue was extracted three times with MTBE. The combined organic phases were dried over MgSO ₄ , filtered and concentrated in vacuo. Purification by column chromatography (silica gel; eluent: MTBE) gave 4.09 g (16.2 mmol, 81% of theory) of a colorless solid.
¹ H-NMR (300 MHz, acetone-d ₆ ): δ = 0.22 (s, 6H; CH ₃ ), 0.99 (s, 9H; tBu), 6.86 (m, 2H; Ar-H), 7.79 (s, 2H; Ar-H)
Elemental analysis: C ₁₂ H ₂₁ BO ₃ Si (252.19):
calc. C 57.15; H 8.39;
found C 60.16; H 8.44.

Claims (17)

1. Process for the preparation of ligands of the formula (I) or (IV)
where m is an integer in the range from 50 to 150, n is an integer in the range from 1 to 5 and z is an integer in the range from 0 to 4,
R ₁ , R ₂ and R _3, independently of one another, are the same or different, and R ₂ and R _{3 are} variable depending on n, H, (C ₁ -C ₅ ) alkyl, linear or branched, (C ₃ -C ₈ ) cycloalkyl , Aryl, aralkyl, alkylaryl or (C ₁ -C ₈ ) alkylalkoxy, linear or branched
and R is a radical of formula (II) or (III)
where R 'can be H, (C ₁ -C ₅ ) alkyl, linear or branched, (C ₃ -C ₈ ) cycloalkyl, aryl, aralkyl or alkylaryl,
is
and of dihydroquinidine derivatives of the formula (IV)
wherein m and o, independently of one another, are identical or different integers in the range from 50 to 150, n and p, independently of one another, are identical or different integers in the range from 1 to 5 and z and y, independently of one another, are identical or different integers in the range from 0 to 4 are and
R, R ₁ , R ₂ and R _{3 have} the meaning given for formula (I), where R ₂ and R _{3 are} additionally variable as a function of o,
characterized by
that intermediates of formula (V) or (VI),
in which R is a radical of the formula (II) or (III)
where R 'can be H, (C ₁ -C ₅ ) alkyl, linear or branched, (C ₃ -C ₈ ) cycloalkyl, aryl, aralkyl or alkylaryl,
is
with compounds of the formula (VII),
wherein m, n and z and R ₁ , R ₂ and R _{3 have} the meaning given for (I) and (IV),
to be esterified. 2. The method according to claim 1, characterized in that the intermediates of the formulas (V) or (VI) by reaction of compounds of the formulas (VIII) and (IX)
in which R is a radical of the formula (II) or (III),
with a compound of formula (X)
in the presence of catalytic amounts of palladium and subsequent silyl group cleavage with fluoride-containing reagents. 3. The method according to claim 2, characterized, that the catalytically active palladium Oxidation level ± 0 and with triphenylphosphine or triphenylphosphite ligand is complexed. 4. The method according to claim 3, characterized in that the compound of formula (XI) as catalytically active palladium
[Pd (PPH ₃ ) ₄ ] (XI)
is used. 5. The method according to claim 2, characterized, that one as a silyl group-releasing reagents or used several tetraalkylammonium fluorides. 6. The method according to claim 5, characterized, that one uses tetrabutylammonium fluoride.   7. The method according to one or more of claims 2-6, characterized in that the compounds of the formulas (VIII)
by reaction of substances of the formula (XII)
with DHQ (II) or DHQD (III). 8. The method according to one or more of claims 2-6, characterized in that the compound of formula (IX)
by reaction of substances of the formula (XIII)
with DHQ (II) or DHQD (III). 9. Ligands of the general formula (I)
wherein m is an integer in the range from 50 to 150, n is an integer in the range from 1 to 5, and z is an integer in the range from 0 to 4,
R ₁ , R ₂ and R _3, independently of one another, are the same or different, and R ₂ and R _{3 are} variable depending on n, H, (C ₁ -C ₅ ) alkyl, linear or branched, (C ₃ -C ₈ ) cycloalkyl , Aryl, aralkyl, alkylaryl or (C ₁ -C ₈ ) alkylalkoxy, linear or branched
and R is a radical of the formula (II)
or a radical of the formula (III)
is
where R 'can be H, (C ₁ -C ₅ ) alkyl, linear or branched, (C ₃ -C ₈ ) cycloalkyl, aryl, aralkyl or alkylaryl. 10. Ligands of the formula (IV)
wherein m and o, independently of one another, are identical or different integers in the range from 50 to 150, n and p, independently of one another, are identical or different integers in the range from 1 to 5 and z and y, independently of one another, are identical or different integers in the range from 0 to 4 are and
R, R ₁ , R ₂ and R _{3 have} the meaning given for formula (I), where R ₂ and R _{3 are} additionally variable as a function of o,
and R is a radical of the formula (II)
or a radical of the formula (III)
is
where R 'can be H, (C ₁ -C ₅ ) alkyl, linear or branched, (C ₃ -C ₈ ) cycloalkyl, fully or partially unsaturated, aryl, aralkyl or alkylaryl. 11. Use of the compounds of the formula (I) or (IV), for the enantioselective dihydroxylation of Double bonds. 12. Use according to claim 11, characterized, that the compounds of formulas (I) and (IV) according to  Dihydroxylation precipitated by filtration from Reaction mixture are separated and so again in the Reaction can be used. 13. Use according to one or more of claims 11 and 12, characterized, that the temperature in the dihydroxylation between -20 ° and + 20 ° C. 14. Use according to one or more of claims 11 to 13, characterized, that the dihydroxylation in one Solvent mixture comprising one or more Group solvents, water, alcohols such as Methanol, ethanol, isopropanol, n-propanol, n-butanol, sec-butanol, tert-butanol, isobutanol, n-pentanol, Ethers such as diethyl ether, tetrahydrofuran, Dimethoxyethane, dioxane, ketones such as acetone, Methyl isobutyl ketone, ethyl ketone, diisopropyl ketone or Esters such as acetoacetic ester or ethyl acetate as well halogenated alkanes such as methylene chloride, chloroform, Trichlorethylene performs. 15. Use according to claim 11, characterized, that as an oxidizing agent, potassium hexacyanoferrate, N-methylmorpholine oxide and / or potassium osmate used will. 16. Use according to claim 15, characterized, that potassium hexacyanoferrate and potassium osmate are used will.   17. Use according to claim 15, characterized, that N-methylmorpholine oxide and potassium osmate are used will.